The Na+/Ca2+ Exchanger Mediates the Effects of Oxidative Stress in Hypertension

Remo      George; Todd      Casanova; Kathy      Nugent; M.      Tino Unlap

Abstract

Oxidative stress is characterized by the elevation of reactive oxygen species (ROS) including the superoxide anion, hydrogen peroxide and the hydroxyl radical. In almost all animal models of hypertension and humans, reducing oxidative stress with antioxidants will lower blood pressure and elevating oxidative stress increases the blood pressure. Generation of ROS in the renal vasculature is accomplished through NADPH oxidase which is expressed in macula densa and afferent arterioles (AA) and leads to enhanced arteriolar tone and reactivity which precede the onset of hypertension. The underlying mechanism is proposed to involve enhanced tubuloglomeruar feedback (TGF) through depletion of NO through interaction with superoxide anion in the juxtaglomerular apparatus (JGA) to form peroxynitrite and a number of microvascular mechanisms including abnormal elevation of intracellular calcium concentration ([Ca2+]i) which can lead to an increased vascular tone and remodeling. The Na+/Ca2+ exchanger (NCX) is critical in regulating cytosolic calcium homeostasis and our studies show that oxidative stress-induced dysregulation of cytosolic calcium homeostasis is mediated through increased Ca2+ influx through the NCX, an effect which is more pronounced in cells expressing an NCX isoform that is expressed in Salt Sensitive Dahl rat. Ca2+ influx through the NCX is preceded by elevation of intracellular Na+ (Nai) and membrane depolarization. Because of the proximity of the Na+/K+-ATPase and the NCX in the PLasmERosome, it is likely that oxidative stress-induced [Ca2+]i elevation in AA smooth muscle cells is initiated by oxidative stress-induced inhibition of the Na+/K+-ATPase which increases Nai that leads to membrane depolarization and Ca2+ influx through the NCX.

Keywords: Oxidative stress, sodium calcium exchanger, hypertension, sodium pump, plasmerosome, reactive oxygen species, superoxide, anion, hydrogen peroxide, NADPH oxidase, blood pressure, tubuloglomeruar feedback, juxtaglomerular apparatus, Na+/Ca2+ exchanger, cytosolic calcium homeostasis, peroxynitrite, cardiovascular disease, nicotine adenine dinucleotide phosphate, super oxide dismutase, neuronal nitric oxide synthase, nitrosylation, tyrosine residues, c-type natriuretic peptide, adrenomedullin, Na-K-ATPase, mesangial cells, NCX1 isoform, vascular smooth muscle cells, sarcoplasmic reticulum, cardiac myocytes, ischemia, hypoxia, myocardial damage, antioxidants, epinephrine, norepinephrine levels, E-ouabain